Process for the production of pyridine derivative



United States Pate O PROCESS FOR THE PRODUCTION OF PYRIDINE DERIVATIVEYoshinobn Sato and Hiroshi Mishima,'- Nishisl1inagawa, Shinagawa-ku,Tokyo-to, Japan, assignors to Sankyo Company, Ltd., Tokyo-to, JapanApplication November 20, 1956 Serial No. 623,280

Claims-priority, application'lapan December 16 '1955 2 Claims. (Cl.260-2955) No Drawing.

This invent'on relatestto aprocess for the production of compound whichis useful as'intermediate for the production of therapeutically'valuablecompounds and is represented by the formula Hitherto, for theproduction. of the compound as described above, the following processeshave been tate and diethyl .aminomethyl'ene malonate to produce theproduct represented by the Formula I.

This process Was described in B. 74, 1111, (1941). However,fi-ethoxyacroleindiethyl acetal which is a starting substance in theprocess (A) should be produced from acrolein. The process (A) can not beused in an industrial scale, because the yield offi-ethoxyacroleindiethyl acetal from acrolein is about only 30%. On theother hand, according to the process (B), only so small an amount of thepyridine derivative can be produced that industrial production thereofis impossible.

An essential object of this invention is to provide a process capable ofindustrially producing the compound represented by the Formula Thepresent inventors have found that the compound represented by theFormula I can be obtained directly with high yield by using acrolein asthe starting substance.

According to this invention; acrolein is first reacted with the compoundrepresented by the Formula II in an absolute alcohol, or in the presenceof a catalyst of piperidine HO..--ooo0,11,

NH (II) whereby a mixture of a dihydro-compound represented by theFormula III and the compound represented by the Formula I, as aboveidentified, is produced.

(IE0 0 O 02H; N CH, (In) Patented July 14, 1959 CHO BIC-00001115 H GH:CH4 .NH;

COOCzHa 0000 11 \N CH; \N -0H, Particularly, this invention can bepreferably carried out by reacting acrolein with the compoundrepresented by the'Formula 11 man absolute alcohol in the presence ofpiperidine and then subjecting the thus obtained mixture of thecompounds represented by the general Formulas I and III to oxidation byusing sodium nitrate and sulfuric acid without separation ofdihydro-compound from the reaction mixture.

' Example I 129 g. (1 mol) of ethyl aminocrotonate (II') was dissolvedin 500 ml. of absolute alcohol and then to this solution was added3,g.ofpiperidine. To this mixture obtained as above was added dropwise67 g. (1.2 mol) of acrolein (1) during a'period of three hours withstirring and heating at a temperature between 40 C.-5 0 C. on waterbath. After the addition was completed, the mixture was heated underreflux for about three hours on water bath. The reaction solutionchanged to pale brown from yellow.

Then, alcohol and piperidinewere distilled out and the residue wasdistilled-at a reduced pressure, whereby 105 g. of the compoundrepresented by the Formula III and 15 g. of the compound represented bythe Formula were obtained.

The properties of said former Compound III: Boiling point (8 mm.) C128-130 Melting point (recrystallized with petroleumether) 71-72 Theproperties of said latter Compound IV: Boiling point (11 mm.) C 103-105Melting point of the picrate C 146 105 g. of the Compound HI wasdissolved in 280 ml. of ether to prepare the first solution and 116 g.of sodium nitrate was dissolved in 320 mol of water to prepare thesecond solution. The first and second solutions were mixed and to thismixture was gradually added 420 ml. of 20% H with reflux condenser.After the addition, water layer was separated from the solution and thenthe water layer was extracted with ether after making the solutionalkaline with a solution of caustic soda. After drying, the ether wasdistilled off and the residue was distilled at a reduced pressure,whereby 79 g. of the compound represented by the general Formula IV wasobtained. Yield of the final product represented by the Formula V was 94g. (79+15).

The reaction of this example is as follows:

CEO HC-COOCiH5 H 1 111: Nfiz CH 00001115 COOCzHS l CH CH N 3 N 3 (III')(IV') COOCzHr COOCQHB 1 t CH CH \N a \N S I COOOzH which comprisesreacting acroleiu with a compound having the formula 130-0 0 GIHE inabsolute alcohol in the presence of a catalyst of piperiproduction of apyridine compound dine, whereby a mixture of compounds having thegeneral formulas I C 0 O 02H \N OH; and

I C 0 0 02H \N CH;

are obtained, and then oxidizing said mixture with sodium nitrate andsulfuric acid.

4 t 2. Process for the production of a pyridine compound having thegeneral formula r which comprises reacting acrolein with a compoundhaving the formula SEC-00002115 I CH;

in absolute alcohol in the presence of a catalyst of pipen'dine wherebya mixture of the compounds having the formulas I O O 0 02 5 m CH; and

C O 0 CQHI l are obtained, separating the dihydro compound from saidmixture, and then oxidizing said dihydro compound with sodium nitrateand sulfuric acid.

References Cited in the file of this patent UNITED STATES PATENTS Hearneet a1 Aug. 22, 1950 Gluesenkamp et a1. Mar. 22, 1955

1. PROCESS FOR THE PRODUCTION OF A PYRIDINE COMPOUND HAVING THE FORMULA